Presentation and Discussion of Uncertainty and Variability in IRIS : Assessments ; EPA Screening Evaluation Report


                EPA Screening Evaluation Report
Presentation and Discussion of Uncertainty and Variability in IRIS
                           Assessments
                             July 2000

              National Center for Environmental Assessment
                  Office of Research and Development
                  US Environmental Protection Agency
                          Washington, DC

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AUTHORS, CONTRIBUTORS, AND REVIEWERS

Author
Karen Hogan
IRIS Staff
National Center for Environmental Assessment
Office of Research and Development
US Environmental Protection Agency
Washington, DC
Internal EPA Reviewer
Hugh Tilson
National Health and Environmental Effects Research Laboratory
Office of Research and Development
US Environmental Protection Agency
Research Triangle Park, NC

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List of Tables

Table 1:  •    Upper 95% bounds on 0% responses for selected toxicity study group sizes

Table 2:      Criteria for classifying extent of presentation and discussion of variability and
             uncertainty

Table 3:      Extent of documentation of variability and uncertainty in a 10% random sample of
             pre-Pilot IRIS Assessments.

Table 4:      Extent of documentation and variability in post-Pilot IRIS Assessments

Table 5:      Correspondence between two independent assignments of IRIS assessments to
             categories of extent of documentation of variability and uncertainly.

Appendix A:  Summary of classifications for screening sample of IRIS assessments

Appendix B:  Independent verification of assignments to documentation categories
                                           111

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Summary

In support of the study that Congress has directed EPA to conduct (via HR-106-379),
evaluating the extent of documentation of uncertainty and variability in IRIS assessments, EPA
has carried out a screening of 67 of the 536 IRIS assessments on-line as of 1/31/2000. The
purpose of this screening is to survey broadly the extent of this documentation in IRIS
assessments, in order to facilitate an in-depth evaluation of a smaller, but representative set of
IRIS assessments, to be carried out by a contractor. A simple random sample comprising 10% of
the pre-Pilot IRIS assessments (52/522), plus all of the 15 Pilot and post-Pilot IRIS assessments
were stratified into three categories, those with none/ minimal, some/ moderate, or extensive
presentation and discussion of uncertainly and variability. This report summarizes this screening
effort.
Introduction/Background

As pointed out in Science and Judgment in Risk Assessment (NRC, 1994) EPA has
historically incorporated uncertainty in health risk assessments in a qualitative manner. There are
no quantitative uncertainty analyses documented or referenced in IRIS. EPA formally stated its
position in the Policy for Use of Probabilistic Analysis in Risk Assessment (1997):

For human health risk assessments, the application of Monte Carlo and other probabilistic
techniques has been limited to exposure assessments in the majority of cases. The current
policy, Conditions for Acceptance and associated guiding principles are not intended to
apply to dose response evaluations for human health risk assessment until this application
of probabilistic analysis has been studied further.

The information provided in IRIS concerning variability and uncertainty has gradually
become more extensive as experience was gained in the IRIS program. At first, IRIS assessments
mainly provided the results of the deliberations culminating in consensus health hazard
conclusions. Gradually the assessments included more of the details of the data and of the
considerations which led to the consensus conclusions.

Note that some general aspects of the extent of variability and uncertainty can be
determined from the IRIS assessments. Concerning variability, upper bounds on response rates,
when provided in the IRIS Summary. A few examples for RfDs and RfCs generated from
NOAELS are provided in Table 1. For instance, for an RfC or RfD determined from a study with
6 animals per group, from which a NOAEL was identified, the 95% upper bound on the observed
0% response rate is approximately 50%. While this does not provide a confidence limit for the
corresponding exposure level, it demonstrates that there is considerable variability (and
uncertainty) in such a NOAEL. Also, the definition of RfDs and RfCs, accessible through the
IRIS Web Site, points out that mere is perhaps an order of magnitude of uncertainty associated
with these determinations.
-1-

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The goal of this study is to examine more closely the strengths and weaknesses of the
documentation of the health hazard assessment conclusions available through IRIS, by examining
specific, representative IRIS assessments. On the advice of the Executive Committee of the
Science Advisory Board (11/29/99), the extent of documentation of variability and uncertainty in
IRIS assessments was established in two steps. The first step was to classify a random sample of
IRIS assessments into categories of documentation: none or minimal, some or moderate, or
extensive. Then assessments randomly drawn from these categories or strata are to be examined
in depth for their treatment of variability and uncertainty, given ihe state of the science and data
available at the time of the assessment.

Stratified random sampling is an efficient method for characterizing a population.
Through selection of strata which are reasonably internally homogeneous, we can expect that a
small number of assessments randomly chosen from'a stratum can represent that stratum. Due to
the large number of pre-Pilot assessment, however, it is not possible to stratify the entire IRIS
database. A smaller subset must be used to characterize the overall extent of documentation of
uncertainty and variability in IRIS. The SAB recommended a 10% sample (52/522), which
NCEA also believes can adequately characterize the entire set of pre-Pilot IRIS assessments for
this evaluation. Thorough attention has been given during the entire IRIS program to generating
consistent summaries of adverse health effects associated with the chemicals considered.
Methods

The goal of the screening was to classify a random sample of assessments according to
the extent of the presentation and discussion of variability and uncertainty.

Selection of Screening Sample The total number of available IRIS assessments was fixed
by focusing on the chemicals listed on the IRIS Website. All toxicity values that were addressed
for each chemical - RfD, RfC, or cancer slope factors - were considered together. There were
522 pre-Pilot IRIS assessments available on-line as of 1/31/2000. These were numbered 1
through 522, in the order that the chemicals appear on-line, alphabetically. A table of random
numbers (Daniel, 1978) was used to select 52 numbers between 1 and 522, inclusive. Computer-
generated random numbers would have been appropriate, but this traditional method is more
straightforward to document. All post-Pilot assessments were stratified, since there were
relatively few post-Pilot assessments, and pre-Pilot and post-Pilot assessments are to be
compared.

Criteria for Assigning Assessments to Strata Since the available assessments were
generated over a period of approximately 14 years, it became clear that there was a continuum of
relevant factors to consider. NCEA developed criteria (see Table 2) to describe the degree of the
documentation and distinguish between qualitative and quantitative aspects of variability and
uncertainty. The first category, None/Minimal, describes assessments which presented results and
overall uncertainty and confidence conclusions, but no incidence rates or other quantitative effect
-2-

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levels for the available studies, nor rationale for the conclusions. Assessments with Some or
Moderate documentation contained quantitative effect levels and some discussion of variability of
effects, including variability across dose groups and temporal variability. In addition, there was
some discussion of the reasons for overall confidence in the assessment. Assessments with
Extensive documentation contained quantitative variability information, some comparison of
results across related studies, discussion of sources of uncertainty, comparison of uncertainties
across available studies, and rationales for confidence in the available studies and conclusions
drawn in the assessment.

In some cases, assessments contained somewhat more documentation of uncertainties
relative to variability, or vice versa. This was apparent within some sections addressing a health
hazard measure (RfC, RfD, or cancer unit risk), and between measures, especially when they were
completed a few years apart. The overall rating for an assessment was determined by the
characterization of the majority of the subsections. Appendix A provides a brief description of the
rationale for classifying each assessment.

For the purposes of this study, the determination of the extent of the presentation and
discussion of variability and uncertainty was restricted to what was explicitly provided in the on-
line IRIS database for each assessment. Specifically, for the pre-Pilot assessments, only the IRIS
Summary was examined. For the later IRIS assessments, the IRIS Summary and the
Toxicological Review were examined. EPA source documents and literature cited in the
assessments could not be consulted, due to the large volume of materials. Consequently, this
stratification addressed only the overall quality or approach to providing this information in the
on-line assessments, not the completeness of the summarized information nor the cited scientific
literature available at the time of each assessment.

Independent Review of Assignments to Documentation Categories The Executive
Committee of the SAB recommended that the assignment of the assessments in the screening
sample to the broad documentation categories go through an independent verification, to evaluate
the repeatability of the decision process. An EPA health scientist not routinely involved in IRIS
assessments applied the criteria developed above to the pre-screening sample of 67 assessments.
The report of this independent review is in Attachment A.
Results and Discussion

The results of applying the criteria in Table 2 to the pre-Pilot and the later IRIS
assessments are given in Tables 3 and 4, respectively. Of the 52 pre-Pilot IRIS assessments
screened (Table 3), 3/52 had extensive, 16/52 some or moderate, and 33/52 none or minimal
presentation or discussion of variability and uncertainty. In sharp contrast, assessments carried
out during or after the Pilot nearly unanimously (14/15) showed extensive treatment of variability
and uncertainty (see Table 4).
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As noted earlier, this evaluation was carried out to facilitate choosing assessments for in-
depth reviews. These in-depth evaluations were to cover a range of IRIS entry dates, types of
chemicals, scientific complexities, and toxic endpoints of concern. To that end, the sampled
assessments are listed in Tables 3 and 4 in chronological order within each of the three categories
of documentation., with broad categories of chemicals and critical health endpoints noted.

Note that a few pre-Pilot assessments referred to data which were not summarized in the
assessment, or otherwise included conclusions which were not supported by the available
summary. In these cases, assessments which otherwise fit the Extensive or Some/Moderate
criteria, but clearly omitted available data, were downgraded one category. These choices seemed
justified, since it seemed likely that if these assessments happened to be selected for the in-depth
phase of the evaluation, these deficiencies would be immediately apparent and remarked on.
These instances are noted in Appendix A.

Recall that 8 Pilot and 8 Pilot/post-Pilot assessments were to be randomly selected from
those screened, with 4 each from the Some/Moderate and Extensive categories within each of the
pre-Pilot and post-Pilot sets. As noted above, however, there were fewer than 4 assessments in 2
of the targeted subgroups. Specifically, only three assessments fell in the Extensive subset of the
pre-Pilot assessments sampled, so an additional Some/Moderate assessment must be evaluated
among the pre-Pilot assessments, resulting in a total of 5 Some/Moderate and 3 Extensive pre-
Pilot assessments. Similarly, among the post-Pilot assessments, only one assessment fell in the
Some/Moderate category, so 7 Extensive assessments must be evaluated to complete the in-depth
sample of post-Pilot assessments.

Due to time constraints, the independent verification of the classifications was carried out
after the in-depth assessments needed to be chosen. Overall, agreement was good (see Table 5),
with a Spearman rank correlation coefficient of 0.82 (Lehmann, 1975). Differences in
assignments for individual assessments were primarily due to the second reviewer classifying 11
'borderline' assessments in the next lower category than the first reviewer had. Also, there were
4 assessments which the first reviewer downgraded for omitting information referenced elsewhere
in the assessment; by the standards of the time the assessments were incomplete. The second
reviewer did not downgrade these assessments, emphasizing the quality of the approach to
presenting variability and uncertainty.

The second reviewer reached equally valid conclusions. Recognizing the subjectiveness
involved in drawing clear distinctions among characterizations which must consider a number of
heterogeneous issues, it is therefore constructive to consider the results of the two rankings
simultaneously. Among pre-Pilot assessments, approximately three-fourths (63-79%, from Table
5) contained none to minimal documentation of variability and uncertainty information. Note that
the vast majority of these assessments were completed before 1990 (see Table 3). Assessments
containing some to moderate documentation represented about 15-31% (Table 5) of the sample.
These were completed uniformly throughout the pre-Pilot period, at least among the assessments
in the screening sample.
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       The distribution of assessments with extensive documentation of variability and
uncertainty clearly increased with time. Virtually all of the Pilot/ppst-Pilot (starting in 1995)
assessments demonstrated extensive treatment of variability and uncertainty information (93-
100%, Table 5). The earliest "Extensive" assessment in the screening sample was either 1,2-
dibromo-3-chloropropane (1991), according to the first reviewer, or manganese or 2,4-/2,6-
toluene diisocyanate mixture (1995), which both reviewers agreed upon.
References

Daniel, Wayne W.  (1978). Biostatistics: A Foundation for Analysis in the Health Sciences.
John Wiley & Sons: New York.

Lehmann, E. L. (1975). Nonparametrics: Statistical Methods Based on Ranks. San Francisco:
Holden-Day, Inc.

National Research Council (1994).  Science and Judgment in Risk Assessment. Washington,
D.C.: National Academy Press

U.S. EPA. (1986) Guidelines for carcinogen risk assessment. Federal Register 51(185):33992-
34003.

U.S. Environmental Protection Agency.  (1996) Proposed guidelines for carcinogen risk
assessment, Notice, 1996.  Federal Register 61(79):17960-18011.

US Environmental  Protection Agency (1997). Policy for Use of Probabilistic Analysis in Risk
Assessment.  National Center for Environmental Assessment: Washington, DC.
                                           -5-

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Table 1 : Upper 95% bounds on 0%
responses for selected toxicity study group
sizes
Animals/sex/group
4
6
20
50
Upper 95% bound on
observed 0% response
60%
46%
17%
7%
Table 2: Criteria for classifying extent of presentation and discussion of variability and
uncertainty
Category
None/
Minimal
Some/
Moderate
Extensive
Variability
Any studies relevant to the conclusions
are listed, only qualitative dose-
responses indicated; no discussion.
Conditions for Minimal met, plus
adverse effect levels provided for
principal study; some discussion.
Conditions for Some/ Moderate met,
plus measures of variability or
discussion of variability of the results.
Uncertainty
Uncertainty factors listed, and overall
confidence stated; no discussion.
Uncertainty factors listed; some
discussion of uncertainty and
confidence in the assessment.
Discussion of the strengths and
weaknesses of the available studies,
some assessment of the level of
confidence in the body of evidence.
-6-

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Appendix B - Independent Review of Assignments to Documentation Categories
July 14,2000
Reviewer: Hugh -Tilson
Chemical
Variability
                                                     Uncertainty
Acetonitrile
   Overall Rating-Extensive based on variability and uncertainty narrative in the Toxicological Review
Aldicarb sulfone
   RFD                       Moderate                    Mimimal
   RfC-Not listed              Not scored                  Not scored
       Moderate
       Not scored
      Not scored
                                                         Not scored
                              Minimal
                              Not Scored
                              Moderate
                               Extensive
                               Not Scored
                               Extensive
                                    Minimal
                                  Not scored
                                  Minimal
                                   Moderate
                                   Not scored
                                   Extensive
   Cancer-Not listed
   Overall Rating-Minimal
Apollo
   RfD
   RfC-Not listed
   Cancer
   Overall Rating-Minimal
Arsenic, inorganic
   RfD
   RfC-Not listed
   Cancer
   Overall Rating-Extensive
Barium and compounds
  Overall Rating-Extensive for both variability and uncertainty based on Toxicological Review
Benomyl
   RfD                        Minimal                      Minimal
   RfC-Not listed              Not Scored                  Not Scored
   Cancer-Not listed            Not Scored                  Not Scored
   Overall Rating-Minimal
Bentazon
   Overall Rating-Extensive for both variability and uncertainty based on Toxicological Review
Benzene
    Overall Rating-Extensive for both variability and uncertainly based on Support Documents on IRIS
Beryllium and compounds
   Overall Rating-Extensive for both variability and uncertainty based on Toxicological Review
beta-Chloronaphthalene
   RfD
   RfC-Not listed
   Cancer-Not listed
   Overall Rating-Minimal
Bis(chloromethyl)ether
   RfD-Not listed
   RfC-Not listed
   Cancer
   Overall Rating-Moderate
Butylphthalyl butylglycolate
   RfD
   RfC-Not listed
   Cancer-Not listed
Overall Rating-Minimal
                               Minimal
                              Not Scored
                              Not Scored
                              Not scored
                              Not scored
                              Moderate
                              Minimal
                              Not scored
                              Not scored
                                      Minimal
                                    Not Scored
                                   Not Scored
                                    Not scored
                                    Not scored
                                    Minimal
                                      Minimal
                                    Not scored
                                    Not scored
                                                B-l
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Appendix B - Independent Review of Assignments to Documentation Categories
July 14,2000
Reviewer Hugh Tilson

Chemical              Variability                      Uncertainty
 Carboxin
   RfD                       Minimal                      Minimal
   RfC-Not listed             Not scored                    Not scored
   Cancer-Not listed           Not scored                    Not scored
   Overall Rating-Minimal
Chlordane
  Overall Rating-Extensive for both variability and uncertainty based on Toxicological Review
Chlorocyclopentadiene
   RfD-Not listed             Not scored                    Not scored
   RfC-Not listed             Not scored                    Not scored
   Cancer                   Minimal •                     Minimal
   Overall Rating-Minimal
Chlorsulfuron
   RfD                       Minimal                      Minimal
   RfC-Not listed             Not scored                    Not scored
   Cancer-Not listed           Not scored                    Not scored
   Overall Rating-Minimal
Chromium III, insoluble salts
  Overall Rating-Extensive for both variability and uncertainty based on Toxicological Review
Chromium VI
  Overall Rating-Extensive for both variability and uncertainty based on Toxicological Review
Cumene
  Overall Rating-Extensive for both variability and uncertainty based on Toxicological Review
Cypermethrin
   RfD                       Minimal                     Minimal
   RfC-Not listed             Not scored                   Not scored
   Cancer-Not listed           Not scored                   Not scored
   Overall Rating-Minimal
Cyromazine
   RfD                        Minimal                     Minimal
   RfC-Not listed              Not scored                  Not scored
   Cancer-Not listed            Not scored                  Not scored
   Overall Rating-Minimal
Danitol
   RfD                        Moderate                   Minimal
   RfC-Not listed              Not scored                  Not scored
   Cancer-Not listed            Not scored                  Not scored
   Overall Rating-Moderate
Dibromo-3-chloropropane, 1,2-
   RfD-Not listed             Not  scored                  Not scored
   RfC                       Moderate                    Minimal
   Cancer-Not listed           Not scored                   Not scored
   Overall Rating-Moderate
Dibromobenzene, 1,4-
   RfD                       Minimal                     Minimal

                                                B-2

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Appendix B - Independent Review of Assignments to Documentation Categories
My 14, 2000
Reviewer: Hugh Tilson
Chemical
   RfC-Not listed
   Cancer-Not listed
   Overall Rating-Minimal
Dibromodichloromethane
   RfD-Not listed
   RfC-Not listed
   Cancer
                       Variability
                            Not scored
                            Not scored
Uncertainty
  Not scored
  Not scored
                            Not scored                   Not scored
                            Not scored                   Not scored
                            Minimal                      Minimal
   Overall Rating-Minimal (on the basis that a classification was made without presenting data)
Dichlorodiphenyltrichloroethane, p,p'-
                            Minimal
                            Not scored
   RfD
   RfC-Not listed
   Cancer                   Minimal
   Overall Rating-Minimal
Dieldrin
   RfD                      Minimal
   RfC-Not listed             Not scored
   Cancer                   Minimal
   Overall Rating-Minimal
Dimethyl phthalate
   RfD-Not listed             Not scored
   RfC-Not listed             Not scored
   Cancer                   Minimal
   Overall Rating-Minimal
Dimethylfbrmamide, N,N-
   RfD-Not listed             Not scored
   RfC                     Moderate
   Cancer-Not listed         Not scored
   Overall Rating-Moderate
Dinitrobenzene, o-
   RfD-Not listed
   RfC-Not listed
   Cancer
    Minimal
   Not scored
    Minimal
                                                          Minimal
                                                        Not scored
                                                         Minimal
                                                        Not scored
                                                        Not scored
                                                         Minimal
                                                       Not scored
                                                       Minimal
                                                       Not scored
                            Not scored                  Not scored
                            Not scored                  Not scored
                            Minimal                     Minimal
   Overall Rating-Minimal (classified as non carcinogenic, supporting data are largely mechanistic and
      not described in detail)
Diphenamid
                           Minimal                      Minimal
                           Not scored                   Not scored
                          Not scored                    Not scored
   RfD
   RfC-Not listed
   Cancer-Not listed
   Overall Rating-Minimal
Ethylene glycol
   RfD                    Minimal
   RfC-Not listed           Not scored
   Cancer-Not listed        Not scored
   Overall Rating-Minimal
Ethylene glycol monobutyl ether
                                                        Minimal
                                                       Not scored
                                                       Not scored
                                               B-3
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Appendix B - Independent Review of Assignments to Documentation Categories

July 14,2000
Reviewer: Hugh Tilson

Chemical              Variability                     Uncertainty
  Overall Rating-Extensive for both variability and uncertainty based on lexicological Review
Fluorine (soluble fluoride)
   RfD                   Minimal                      Minimal
   RfC-Not listed           Not scored                   Not scored
   Cancer-Not listed       Not scored           -        Not scored
   Overall Rating-Minimal
Fomesafen
   RfD-Not listed           Not scored                   Not scored
   RfC-Not listed           Not scored                   Not scored
   Cancer                 Minimal                      Minimal
   Overall Rating-Minimal
Furmecyclox
   RfD-Not listed           Not scored                   Not scored
   RfC-Not listed           Not scored                   Not scored
   Cancer                 Minimal                      Minimal
   Overall Rating-Moderate
Hexachlorobenzene
   RfD                   Minimal                      Minimal
   RfC-Not listed           Not scored                   Not scored
   Cancer                 Minimal                      Minimal
   Overall Rating-Minimal
Hexachlorodibenzo-p-dioxin, mixture
   RfD-Not listed          Not scored                    Not scored
   RfC-Not listed          Not scored                    Not scored
   Cancer                Minimal                       Minimal
   Overall Rating-Minimal
Hexachlorophene
   RfD                  Minimal                       Minimal
   RfC-Not listed          Not scored                    Not scored
   Cancer-Not listed      Not scored                     Not scored
   Overall Rating-Minimal
Hexazinone
   RfD                  Minimal                       Minimal
   RfC-Not listed          Not scored                    Not scored
   Cancer-Not listed  '   Not scored                    Not scored
   Overall Rating-Minimal
Maneb
   RfD                 Minimal                       Minimal
   RfC-Not listed         Not scored                    Not scored
   Cancer-Not liested    Not scored                     Not scored
   Overall Rating-Minimal
Manganese
   RfD
   RfC
   Cancer
 Moderate
 Extensive
Not scored (moderate narrative)

                        B-4
  Extensive
  Extensive
Not scored (not carcinogenic)

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Appendix B - Independent Review of Assignments to Documentation Categories

July 14,2000
Reviewer: Hugh Tilson

Chemical              Variability                      Uncertainty
   Overall Rating-Extensive
Metalaxyl
   RfD                 Minimal                        Minimal
   RfC-Not listed       Not scored                     Not scored
   Cancer-Not listed     Not scored                    Not scored
   Overall Rating-Minimal
Methamidophos
   RfD                 Minimal                       Minimal
   RfC-Not listed       Not scored                    Not scored
   Cancer-Not listed    Not scored                     Not scored
   Overall Rating-Minimal
Methyl methacrylate
   Overall Rating- Extensive for both variability and uncertainty based on Toxicological Review
Methylene diphenyl diisocyanate
   Overall Rating- Extensive for both variability and uncertainty based on Toxicological Review
Methylphenol, 4-
   RfD-Withdrawn      Not scored                    Not scored
   RfC-Not listed       Not scored                    Not scored
   Cancer             Moderate                     Minimal
   Overall Rating- Moderate
Naphthalene
   Overall Rating-Extensive based on both variability and uncertainty in Toxicological Review
N-Nitroso-N-methylethylamine
   RfD-Not listed       Not scored                   Not scored
   RfC-Not listed       Not scored                   Not scored
   Cancer             Moderate                    Minimal
   Overall Rating- Moderate
Octabromodiphenyl ether
   RfD                 Minimal                     Minimal
   RfC-Not listed       Not scored                   Not scored
   Cancer-Not care.     Not scored                   Not scored
   Overall Rating-Minimal
Pentachlorophenol
   RfD                 Minimal                     Minimal
   RfC-Not listed       Not scored                  Not scored
   Cancer             Moderate                    Minimal
   Overall Rating-Minimal
Phosmet
   RfD                 Minimal                     Minimal
   RfC                Not scored                  Not scored
   Cancer             Not scored                  Not scored
   Overall Rating-Minimal
Prochloraz
   RfD                Minimal                     Minimal
   RfC-Not listed       Not scored                  Not scored

                                               B-5
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Appendix B - Independent Review of Assignments to Documentation Categories
July 14,2000
Reviewer: Hugh Tilson
Chemical
 Variability
Moderate
    Uncertainty
Minimal
   Cancer
   Overall Rating-Minimal
Pronamide
   RfD                Minimal                    Minimal
   RfC-Not listed        Not scored                 Not scored
   Cancer-Not listed     Not scored                 Not scored
   Overall Rating-Minimal
Propargite
   RfD                Minimal                    Minimal
   RfC-Not listed        Not scored                 Not scored
   Cancer              Not scored                 Not scored
   Overall Rating-Minimal
Pursuit
   RfD                Minimal                   Minimal
   RfC-Not listed        Not scored                 Not scored
   Cancer-Not listed     Not scored                Not scored
   Overall Rating-Minimal
Pydrin
   RfD                 Minimal                   Minimal
   RfC-Not listed        Not scored                 Not scored
   Cancer-Not listed     Not scored                 Not scored
   Overall Rating-Minimal
Sodium azide
   RfD                 Minimal                   Minimal
   RfC-Not listed        Not scored                 Not scored
   Cancer-Not listed     Not scored                 Not scored
   Overall Rating-Minimal
Tetrachlorovinphos
   RfD                Minimal                   Minimal
   RfC-Not listed        Not scored                 Not scored
   Cancer-Not listed     Not scored                 Not scored
   Overall Rating-Minimal
Toluene diisocyanate mixture, 2,4-72,6-
   RfD-Not listed        Not scored                 Not scored
   RfC-               Extensive                 Moderate
   Cancer-Not listed     Not scored                 Not scored
   Overall Rating-Extensive
Tributyltin oxide
   Overall Rating-Extensive based on variability and uncertainty in lexicological Review
Trichloroethane, 1,1,1-
   RfD-Not listed        Not scored         '       Not scored
   RfC-Not listed        Not scored                 Not scored
   Cancer-             Minimal                   Minimal
   Overall Rating-Minimal
Triethylene glycol monobutyl ether
                                               B-6
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 Appendix B - Independent Review of Assignments to Documentation Categories

.My 14,2000
 Reviewer: Hugh Tilson
 Chemical
    RfD-Not listed
    RfC-Not verifiable
    Cancer-Not listed
 Variability
 Not scored
 Minimal
Not scored
     Uncertainty
Not scored
  Minimal
Not scored
    Overall Rating-Minimal
 Trinitrobenzene, 1,3,5-
    Overall Rating-Extensive on the basis of narrative for variability and uncertainty in the Support Document
 Vanadium pentoxide                            t
    RfD                 Minimal                     Minimal
    RfC-Not listed        Not scored                  Not scored
    Cancer-Not listed .    Not scored                  Not scored
    Overall Rating-Minimal
 Vinyl acetate
    RfD-Not listed        Not scored                  Not scored
    RfC                 Moderate                    Minimal
    Cancer-Not listed     Not scored                  Not scored
    Overall Rating-Moderate
 Criteria for Classification:

                Variability
 Minimal        No incidence generally
                provided for RfD/RfC
 Moderate       Incidence, magnitude, onset
                or duration mentioned with
                some discussion, little discusion
                about varability within or across
                studies

 Extensive       Incidence, magnitude, onset
                and duration mentioned
                repeatedly; considerable discus-
                sion about sources of variability
                across and within studies
                                Uncertainty
                                Relatively terse description of what the
                                uncertainty factors were with little or
                                no discussion about their rationale;
                                no discussion about strengths or weaknesses

                                Rationale developed for the selection
                                of the uncertainty factors, strengths
                                or weaknesses mentioned
                                Considerable rationale for confidence
                                in studies and support provided for
                                conclusions, strengths or weaknesses
                                discussed
         In some cases, assessments contained somewhat more documentation of uncertainties relative to
 variability, and vice versa. If only one area qualified as Extensive, then the entire assessment was categorized as
 Extensive. At the other end of the scale, if one part of an assessment contained Moderate documentation, the entire
 assessment was categorized as Moderate. Several assessments were based on Supporting Documents or
 lexicological Reviews located on IRIS. All of these were categorized as Extensive.
                                                  B-7
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